Dynamic incorporation of histone H3 variants into chromatin is essential for acquisition of aggressive traits and metastatic colonization

Carcinomas can acquire metastatic potential by undergoing a cellular program referred to as epithelial-to-mesenchymal transition (EMT). During EMT, the genome undergoes major epigenetic changes required for the expression of genes that promote cell motility, invasiveness, and survival under stress. While recent data point to a crucial role of chromatin remodeling in this process, little is known about the nature of this remodeling and the signals that trigger it. Here we show that metastasis-inducing pathways regulate histone chaperones to reduce canonical histone incorporation into chromatin. This triggers deposition of H3.3 to the promoters of EMT-inducing transcription factors and poor prognosis genes, a phenomenon that is sufficient and necessary for the induction of EMT and metastasis. Together, we have discovered histone H3.3 variant as a major regulator of cell fate during tumorigenesis and histone chaperones as valuable therapeutic targets for metastatic disease. Global analysis of RNA levels to determine transcriptional reprogramming in MCF-10A cells upon CAF-1 suppression, in triplicate

癌组织可通过启动名为上皮间质转化（epithelial-to-mesenchymal transition, EMT）的细胞程序获得转移潜能。在EMT过程中，基因组会发生一系列重大表观遗传变化，这些变化是驱动细胞运动、侵袭及应激存活相关基因表达的必要条件。尽管近期研究表明染色质重塑（chromatin remodeling）在此过程中发挥关键作用，但学界对该重塑的本质及其触发信号仍知之甚少。本研究发现，诱导肿瘤转移的信号通路可通过调控组蛋白伴侣（histone chaperones），减少经典组蛋白（canonical histone）在染色质中的整合。这一过程会促使组蛋白H3.3沉积至EMT诱导转录因子及预后不良基因的启动子区域，而该现象是诱导EMT与转移的充分必要条件。综上，本研究证实组蛋白H3.3变体（histone H3.3 variant）是肿瘤发生过程中调控细胞命运的核心因子，同时发现组蛋白伴侣可作为转移性疾病的潜在治疗靶点。本研究通过三次生物学重复，对CAF-1抑制后的MCF-10A细胞开展了全局RNA水平分析，以明确其转录重编程（transcriptional reprogramming）情况。